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REACTIONS OF ALKYL HALIDES: NUCLEOPHILIC SUBSTITUTION AND ELIMINATION Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8 th ed.) sections 10.1, 11.1-11.5, 11.7-11.10,

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Presentation on theme: "REACTIONS OF ALKYL HALIDES: NUCLEOPHILIC SUBSTITUTION AND ELIMINATION Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8 th ed.) sections 10.1, 11.1-11.5, 11.7-11.10,"— Presentation transcript:

1 REACTIONS OF ALKYL HALIDES: NUCLEOPHILIC SUBSTITUTION AND ELIMINATION Dr. Sheppard CHEM 2412 Fall 2014 McMurry (8 th ed.) sections 10.1, , , 11.12

2 Alkyl Halides Contain F, Cl, Br, or I Widely used in: Synthesis (electrophilic carbon and easy functional group transitions) Solvents (CCl 4, CHCl 3, CH 2 Cl 2 ) Industrial applications Structure:

3 Properties of Alkyl Halides Bond strength Measured by bond dissociation energy Inversely proportional to bond length Electronegativity and small size of F keep bonding electrons close C-F > C-Cl > C-Br > C-I short long strong weak Which C-X bond is easier to break, C-Cl or C-Br?

4 Properties of Alkyl Halides Polarity Alkyl halides have substantial dipole moments Dipole moments depend on: 1. Electronegativity of X F > Cl > Br > I 2. C-X bond length C-I > C-Br > C-Cl > C-F 3. Polarizability of electrons (ease of distribution of electron density) I > Br > Cl > F Since these trends oppose one another, the trend in molecular dipole moment is not periodic C-Cl > C-F > C-Br > C-I

5 Summary of Alkyl Halide Properties

6 Reactions of Alkyl Halides Carbon bonded to X is electron-poor (electrophilic) Will react with nucleophiles Nucleophiles are also bases! So, there are two competing reactions: 1. Substitution Nucleophile substitutes for X (the leaving group) 2. Elimination Nucleophile/base removes H, eliminates HX to yield an alkene

7 Substitution vs. Elimination How do we know which reaction will occur? In this chapter: I. Mechanisms of substitution II. Mechanisms of elimination III. Substitution vs. elimination

8 I. Nucleophilic Substitution Nucleophile substitute for leaving group (X) Example: CH 3 CH 2 CH 2 Br + NaOCH 3 → CH 3 CH 2 CH 2 OCH 3 + NaBr Leaving group = Nucleophile =

9 Stereochemistry When the product has a stereocenter, we must consider stereochemistry Examples: How can we explain the observed stereochemistry? There is more than one possible mechanism S N 2 and S N 1 (differ in timing of C-X breaking and C-Nu formation)

10 The S N 2 Reaction Bimolecular nucleophilic substitution Bimolecular = two species (RX and Nu) participate in RDS Rate = k [RX] [Nu] Mechanism: Single step No intermediates Bonds broken and made simultaneously (concerted) Same mechanism as acetylide ion and methyl/primary RX

11 Transition State of S N 2 Reaction

12 CH 3 Br + NaOH → Products: Mechanism:

13 S N 2 Energy Diagram One step Exothermic E Reaction Coordinate

14 S N 2 Stereochemistry Nucleophile attacks reaction center (electrophilic carbon) from the direction opposite the leaving group Backside attack Causes change in configuration Stereocenter: S ↔ R Rings: cis ↔ trans Ex: (S)-2-bromobutane + NaOH

15 S N 2 Characteristics Factors influencing the rate of S N 2 reaction: Alkyl halide structure Nucleophile Leaving group Solvent

16 S N 2 Characteristics: RX Structure Steric effects Nucleophile must have access to reaction center Access is hindered with bulky substituents

17 S N 2 Characteristics: RX Structure Trends in RX reactivity: Methyl halide most reactive Tertiary alkyl halide not likely to react Branched 1° and 2° alkyl halides react slower than unbranched Vinyl and aryl halides will not react

18 S N 2 Characteristics: Nucleophile Nucleophile: contains lone pair Some nucleophile are better than others Better nucleophile = faster S N 2 reaction Some common nucleophiles: What trends do you notice relating nucleophilicity and structure? PoorGoodStrong ROH RCO 2 H H 2 O F RCO 2 RSH NH 3 /NR 3 Cl Br I HS HO RO CN

19 Trends in Nucleophile Structure 1. Anions are stronger nucleophiles than neutral molecules HO > H 2 O RO > ROH

20 Trends in Nucleophile Structure 2. Less stable anions are stronger nucleophiles than more stable anions RO > RCO 2 3. Generally, nucleophilicity increases down a group I > Br, Cl > F 4. Bulky anions are more likely to act as a base, rather than a nucleophile (CH 3 ) 3 CO vs. CH 3 O base nucleophile

21 Nucleophile Structure Some common good nucleophiles are also strong bases HO - RO - H 2 N - Some common good nucleophiles are weak bases I - - CN RCO 2 - This will be important later when comparing substitution and elimination

22 S N 2 Characteristics: Leaving Group Better LG = faster reaction Better LG = more stable anion

23 S N 2 Characteristics: Solvent Dissolves reactants, creates environment of reaction, can affect outcome of reaction Solvents are either protic or aprotic Polar protic H-bond donor Contain NH or OH Alcohols, carboxylic acids, amines, water Polar aprotic Cannot donate H-bond Dimethyl sulfoxide (DMSO) Acetone Acetonitrile N,N-Dimethylformamide (DMF)

24 S N 2 Characteristics: Solvent Polar aprotic solvents solvate cations, but not anions Anions shielded from  + by methyl groups Less solvated More available to react as nucleophiles Good for S N 2!

25 S N 2 Characteristics: Solvent Polar protic solvents solvate both cations AND anions Anion is well-solvated Less available to react as nucleophiles Not good for S N 2!

26 S N 2 Summary Rates of Reaction (Kinetics): What is the rate-determining step for the S N 2 reaction? Does the rate of reaction depend on the concentration of alkyl halide only OR both the alkyl halide and nucleophile? Stereochemistry: What happens to a stereocenter (chirality center) during the course of this reaction? Structure of the Alkyl Halide: List alkyl halide type (1 , 2 , 3  ) in order of decreasing ability to undergo this type of substitution reaction. Are there any types of alkyl halides that do not undergo this type of reaction? Why? Given this order or reactivity, are electronic factors important for this reaction? Why or why not? Are steric factors important for this reaction? Why or why not? The Nucleophile: Is the nature of the nucleophile important for the S N 2 reaction? Why or why not? The Leaving Group: Rank the leaving groups of alkyl halides (F -, Cl -, Br -, I - ) in their ability to “leave.” Why is this trend observed? The Solvent: How do polar aprotic solvents and polar protic solvents affect substitution reactions? What are the best solvents for the S N 2 reaction? Why?

27 The S N 1 Reaction Unimolecular nucleophilic substitution Unimolecular = one species (RX) participates in RDS Rate = k [RX] Mechanism: Multiple steps Carbocation intermediate C-X bon broken before C-Nu bond formed Which step is RDS?

28 Mechanism of S N 1 Reaction

29 S N 1 Energy Diagram

30 S N 1 Stereochemistry Racemic mixture 50% inversion of configuration 50% retention of configuration Why? Look at intermediate…

31 (R)-3-chloro-3-methylhexane + NaOAc → Products: Mechanism:

32 S N 1 Stereochemistry Sometimes slightly more than one enantiomer is observed 55-60% inversion 40-45% retention Why? Association of leaving group with carbocation

33 S N 1 Characteristics Factors influencing the rate of S N 1 reaction: Alkyl halide structure Nucleophile Leaving group Solvent

34 S N 1 Characteristics: RX Structure Electronic effects More stable carbocation = faster reaction Remember carbocation stability

35 S N 1 Characteristics: RX Structure Trends in RX reactivity: Tertiary alkyl halides most reactive Primary alkyl halides will not form unless allylic or benzylic

36 S N 1 Characteristics: Nucleophile Nucleophile is not important for S N 1 reactions Not in the rate equation Even poor nucleophiles are OK for S N 1 H 2 O, ROH, etc.

37 S N 1 Characteristics: Leaving Group Better LG = faster reaction

38 S N 1 Characteristics: Leaving Group S N 1 on alcohols Need strong acid to protonate –OH and form a better LG

39 S N 1 Characteristics: Solvent Polar protic solvents = faster reaction Solvate both cations AND anions Speed up RDS by solvating and separating carbocation intermediate and leaving group anion Good for S N 1! Commonly S N 1 nucleophile = solvent Solvolysis reaction

40 S N 1 Summary Rates of Reaction (Kinetics): What is the rate-determining step for the S N 1 reaction? Does the rate of reaction depend on the concentration of alkyl halide only OR both the alkyl halide and nucleophile? Stereochemistry: What happens to a stereocenter (chirality center) during the course of this reaction? Structure of the Alkyl Halide: List alkyl halide type (1 , 2 , 3  ) in order of decreasing ability to undergo this type of substitution reaction. Are there any types of alkyl halides that do not undergo this type of reaction? Why? Given this order or reactivity, are electronic factors important for this reaction? Why or why not? Are steric factors important for this reaction? Why or why not? The Nucleophile: Is the nature of the nucleophile important for the S N 1 reaction? Why or why not? The Leaving Group: Rank the leaving groups of alkyl halides (F -, Cl -, Br -, I - ) in their ability to “leave.” Why is this trend observed? The Solvent: How do polar aprotic solvents and polar protic solvents affect substitution reactions? What are the best solvents for the S N 1 reaction? Why?

41 Summary of S N 2 vs. S N 1 SN2SN2SN1SN1 Driving forceSteric factorsElectronic factors Alkyl halide Methyl 1° 2° Allylic Benzylic 3° 2° Allylic Benzylic Stereochemistry100% inversionRacemic mixture RegiochemistryNo rearrangements Rearrangements possible NucleophileGoodGood or poor SolventAproticProtic

42 Predict the substitution mechanism and products for the following reactions…

43 Carbocation Rearrangements Carbocation intermediates can rearrange to form a more stable carbocation structure Types of rearrangements: Hydride shift Alkyl shift (methyl or phenyl) Can S N 2 reactions undergo rearrangement?

44 Draw the Mechanism…

45 Outline In this chapter: I. Mechanisms of substitution S N 2 S N 1 II. Mechanisms of elimination E2 E1 III. Substitution vs. elimination

46 II. Elimination Reactions Alkyl halide + base → alkene X eliminated from one carbon H eliminated from adjacent carbon Compete with substitution reactions

47 1-Bromobutane + t-BuOK →

48 Elimination Regiochemistry Multiple products can be formed if there is more than one adjacent H How do we know the major product?

49 Zaitsev’s Rule In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates This alkene is more stable There are some exceptions, but this rule is generally true Example: Which product is major?

50 The E2 Reaction Bimolecular elimination Rate = k [RX] [Base] Mechanism: Single step Concerted No intermediates Needs a strong base (NaOH, NaOR, NaNH 2 )

51 E2 Stereochemistry The alkyl halide must have anti-periplanar geometry Anti = H and X on opposite sides of molecule Less steric strain between base and leaving group Periplanar = all 4 reacting atoms (H, C, C, X) are in the same plane Maximizes molecular orbital overlap in transition state

52 What is the major product of E2 reaction of (2S,3R)-2-bromo-3-methylpentane

53 E2 Regiochemistry Usually Zaitsev Formation of non-Zaitsev product: 1. When the base is a bulky base t-BuO - is sterically hindered, does not remove more crowded H

54 E2 Regiochemistry Formation of non-Zaitsev product: 2. When anti-periplanar geometry cannot be achieved (substituted cyclohexanes) Anti-periplanar = trans diaxial

55 cis-1-Chloro-2-isopropylcyclohexane

56 trans-1-Chloro-2-isopropylcyclohexane

57 The E1 Reaction Unimolecular elimination Rate = k [RX] Mechanism: Multiple steps Carbocation intermediate Weak base is OK due to reactive R + intermediate Stereochemistry of RX not a factor due to R + planarity Regiochemistry is Zaitsev

58 2-Methyl-2-chloropropane + CH 3 OH → Products: Mechanism:

59 E1 Reaction of Alcohols Dehydration of an alcohol to form an alkene is also E1 mechanism Reaction is reversible Remove alkene as formed (distillation) to push to the right Acid catalyst is needed H 3 PO 4 or H 2 SO 4 Protonates –OH to make a better leaving group (H 2 O) Example:

60 Summary of E2 vs. E1 E2E1 Alkyl halide 1° 2° 3° 2° BaseStrongWeak StereochemistryAnti-periplanarn/a Regiochemistry Zaitsev, unless bulky base or no anti- periplanar conformation Zaitsev

61 Predict the elimination mechanism and products for the following reactions…

62 Outline In this chapter: I. Mechanisms of substitution S N 2 S N 1 II. Mechanisms of elimination E2 E1 III. Substitution vs. elimination S N 2 or S N 1 or E2 or E1

63 III. Substitution vs. Elimination Given starting material and reagents Predict mechanism and draw products Remember regiochemistry and stereochemistry Where do we start? First, look at possible mechanisms for each RX structure Then, compare reaction conditions for each mechanism

64 Possible Mechanisms RX StructureSN2SN2SN1SN1E2E1 Methyl 1° 2° 3°

65 Reaction Conditions S N 2 vs. S N 1 Good nucleophile and aprotic solvent favor S N 2 Poor nucleophile and protic solvent favor S N 1 E2 vs. E1 Strong base favors E2 Weak base favors E1 S N 2 vs. E2 Good nucleophiles/weak bases favor S N 2 Good nucleophiles/strong bases and 1° RX result in S N 2 and E2 Good nucleophiles/strong bases and 2° RX result in E2 Bulky bases or branched RX favor E2 S N 1 vs. E1 S N 1 and E1 are both favored with weak nucleophiles/bases Mixture of products from both S N 1 vs. E1 will result anytime a unimolecular mechanism is predicted

66 The Magic Chart… Alkyl HalideMechanismConditions MethylSN2SN2  Only option 1° SN2SN2  Weak base/good nucleophile  Strong base, non-bulky (competes with E2) E2  Strong base, non-bulky (competes with S N 2)  Bulky base  Branched RX 2° SN2SN2  Weak base/good nucleophile E2  Strong base S N 1/E1  Weak base/weak nucleophile 3° E2  Strong base S N 1/E1  Weak base Strong bases (non-bulky): HO -, RO -, H 2 N - Bulky base: t-BuO - Weak base/good nucleophile: I -, CN -, CH 3 CO 2 - Weak base/weak nucleophile: ROH, H 2 O, CH 3 CO 2 H (anything neutral)

67 Predict the substitution and/or elimination mechanism and draw products for the following reactions…


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